The invention relates to a method of reducing unwanted hair growth in mammals.
A main function of mammalian hair is to provide environmental protection. However, that function has largely been lost in humans, in whom hair is kept or removed from various parts of the body essentially for cosmetic reasons. For example, it is generally preferred to have hair on the scalp but not on the face.
Various procedures have been employed to remove unwanted hair, including shaving, electrolysis, depilatory creams or lotions, waxing, plucking, and therapeutic antiandrogens. These conventional procedures generally have drawbacks associated with them. Shaving, for instance, can cause nicks and cuts, and can leave a perception of an increase in the rate of hair regrowth. Shaving also can leave an undesirable stubble. Electrolysis, on the other hand, can keep a treated area free of hair for prolonged periods of time, but can be expensive, painful, and sometimes leaves scarring. Depilatory creams, though very effective, typically are not recommended for frequent use due to their high irritancy potential. Waxing and plucking can cause pain, discomfort, and poor removal of short hair. Finally, antiandrogens--which have been used to treat female hirsutism--can have unwanted side effects.
It has previously been disclosed that the rate and character of hair growth can be altered by applying to the skin inhibitors of certain enzymes. These inhibitors include inhibitors of 5-alpha reductase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, gamma-glutamyl transpeptidase, and transglutaminase. See, for example, Breuer et al., U.S. Pat. No. 4,885,289; Shander, U.S. Pat. No. 4,720,489; Ahluwalia, U.S. Pat. No. 5,095,007; Ahluwalia et al., U.S. Pat. No. 5,096,911; Shander et al., U.S. Pat. No. 5,132,293; and Shander et al., U.S. Pat. No. 5,143,925.
Glycoproteins, proteoglycans, and glycosaminoglycans are three related components present in most mammalian tissues including skin and hair follicles.
Glycoproteins are protein molecules with oligosaccharide chains covalently attached to their polypeptide backbone structure. The oligosaccharide chains consist of sugar residues, which may include glucose, galactose, mannose, N-acetylgalactosamine, N-acetylglucosamine, fucose, arabinose, xylose, and sialic acids (example, N-acetylneuraminic acid). The oligosaccharides composed of these nine sugar residues are linked to the protein molecules with either O- or N-glycosidic linkage to form a glycoprotein molecule. The oligosaccharide chain is first synthesized on a lipid carrier, dolichol, and then transferred to the protein molecule to form a glycoprotein.
The synthesis of the oligosaccharide chain on dolichol is carried out in a specific manner in which the sequence of sugar residues is pre-determined by the regulatory enzymes involved in the synthesis. The first step in the synthesis is transfer of N-acetylglucosamine (GlcNAc) to dolichyl-phosphate to form GlcNAc-pyrophosphoryl-dolichyl (GlcNAc-P-P-Dol), which acts as an acceptor for an additional molecule of GlcNAc. Nine molecules of mannose (Man) and three molecules of glucose (Glc) are attached to this molecule to form Glc.sub.3 Man.sub.9 (GlcNAc).sub.2 -PP-dolichol. The completed oligosaccharide chain Glc.sub.3 Man.sub.9 -(GlcNAc).sub.2 ! is then transferred to an acceptor protein catalyzed by an enzyme (oligosaccharide transferase). The oligosaccharide chain on this glycoprotein is further modified by enzymes such as glycosidases to form an active glycoprotein.
It is known that the process of glycoprotein formation (or protein glycosylation) can be inhibited at several steps by using select inhibitors.
For example, the synthesis of N-acetyl-glucosamine-pyrophosphoryl-dolichyl (GlcNAc-P-P-Dol), the first step in lipid linked oligosaccharide formation, is inhibited by antibiotics such as bacitracin, tunicamycin, amphomycin, tsushimycin, diumycin, showdomycin, amphortericine, streptovirudin, and mycospocidin. In addition, the formation of (Glc.sub.3 Man.sub.9 -GlcNAc).sub.2 -PP-dolichol and the protein glycosylation step of transferring the core oligosaccharide chain to the acceptor protein molecule is inhibited by sugar analogs such as 2-deoxy-2-fluoro-mannose, fucose, mannose, D-glucasoamine, N-acetyl-D-glucasomine, and galactose. Also, the modification of the oligosaccharide chain of glycoprotein to form the active glycoprotein is inhibited by inhibitors of glucosidase I and II (e.g., castanospermine, deoxynojirimycin, and methyldeoxynojirimycin), inhibitors of mannosidase I (e.g., deoxymannojirimycin), inhibitors of mannosidase II (e.g., swainsonine). Other inhibitors of the processing include 2,5-dihydroxymethyl-3,4-dihydropyrrolidine, and 1,4-dideoxy-1,4-iminomannitol.
Proteoglycans, like glycoproteins, consist of a core protein molecule covalently attached to glycosaminoglycan (polysaccharide) chain(s). The distinction between proteoglycans and glycoproteins is based on the chemical nature and the arrangement of sugar residues of the attached polysaccharides. Glycosaminoglycan consists of linear polysaccharide chains made of a repeating sequence of an aminosugar hexosamine (D-glucosamine or D-galactosamine) and uronic acid (D-glucuronic acid or L-iduronic acid) residues. At least seven different types of glycosaminoglycans have been identified. Each differs from the others by the nature and/or arrangement of the sugar moieties and the degree of sulfation. Glycosaminoglycans, except hyaluronic acid, typically are synthesized attached to the protein molecule (i.e., as proteoglycans). The chain elongation is initiated by either xylosylation of select serine residues of protein (the xylose-serine bond formed is unique to proteoglycans), or a bond between N-acetylhexosamine (GalNAc or GlcNAc) and either the serine or the asparagine residue of a protein. Additional sugar residues then are added, and are further modified by the introduction of sulfate groups.
The proteoglycans generally are referred to by simple names based on their localization and/or function, or by names based on the attached glycosaminoglycan chains. The common proteoglycans include aggrecan, decorin, syndecan 1, versican, BM-CSPG (basement membrane-chondroitin sulfate containing proteoglycan), perlecan (heparan sulfate proteoglycan), biglycan, and fibromodulin.
The common glycosaminoglycans include chondroitin sulfates, keratan sulfates, dermatan sulfate, heparan sulfate, heparin, and hyaluronic acid. With the exception of hyaluronic acid, which is found as a free polysaccharide, all other glycosaminoglycans typically exist as proteoglycans.
It is known that inhibitors of glycosaminoglycan and proteoglycan formation include xylosides such as nitrophenyl-.beta.-xylopyranoside, nitrophenyl-N-acetyl-.beta.-D-xalactosamide, 4-methylumbelliferyl-.beta.-D-xyloside, and methyl-.beta.-xylopyranoside. These act as artificial acceptors and compete with the core protein molecule for the synthesis of glycosaminoglycan chain, especially at the initial xylosylation step.
Additional compounds that are known to affect one or more steps in the synthesis of glycoproteins, glycosaminoglycans, and proteoglycans include an ionophore monensin, which inhibits the terminal glycosylation reaction; inhibitors of .beta.-galactosidase like benzyl-N-acetyl-.beta.-D-galactosamide, phenyl-N-acetyl-.beta.-D-galactosamide, and nitrophenyl-N-acetyl-.beta.-D-galactosamide; and compounds that affect exocytosis (release) of proteoglycans, like diethylcarbamazine.